A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers

• Published in: Haematologica (Roma) Vol. 999; no. 1
• Main Authors: Spriano, Filippo, Sartori, Giulio, Sgrignani, Jacopo, Barnabei, Laura, Arribas, Alberto J., Guala, Matilde, Del Amor, Ana Maria Carrasco, Tomasso, Meagan R., Tarantelli, Chiara, Cascione, Luciano, Golino, Gaetanina, Riveiro, Maria E, Bortolozzi, Roberta, Lupia, Antonio, Paduano, Francesco, Huguet, Samuel, Rezai, Keyvan, Rinaldi, Andrea, Margheriti, Francesco, Ventura, Pedro, Guarda, Greta, Costa, Giosuè, Rocca, Roberta, Furlan, Alberto, Verdonk, Luuk M., Innocenti, Paolo, Martin, Nathaniel I., Viola, Giampietro, Driessen, Christoph, Zucca, Emanuele, Stathis, Anastasios, Gahtory, Digvijay, Van den Nieuwboer, Maurits, Bornhauser, Beat, Alcaro, Stefano, Trapasso, Francesco, Cristobal, Susana, Padrick, Shae B., Pazzi, Natalina, Cavalli, Franco, Cavalli, Andrea, Gaudio, Eugenio, Bertoni, Francesco
• Format: Journal Article
• Language: English
• Published: Ferrata Storti Foundation 20.06.2024
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2022.282672

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.